The Agricultural Health Study (AHS) is a long-term prospective study of potential health effects associated with pesticides and other agricultural exposures. The study is funded by the National Cancer Institute and the National Institute of Environmental Health Sciences, with collaboration from the US Environmental Protection Agency and the National Institute for Occupational Safety and Health. We are examining cancer and other health endpoints in licensed pesticide applicators (mostly farmers), their spouses and children from North Carolina (NC) and Iowa (IA). Between 1993 and 1997, we enrolled more than 57,000 licensed applicators, 82% of eligible private pesticide applicators (largely farmers) in IA and NC and 43% of commercial applicators from Iowa. About 40% of the private applicators completed a more detailed take-home questionnaire covering farming practices and health. Nearly 32,000 spouses of farmer applicators enrolled and provided data on pesticides and health (including reproductive health), and children under age 21 at time of enrollment. Study participants have completed up to three follow-up surveys in 1999-2003, 2005-2010, and 2013-2015, updating data on farming exposures and lifestyle and the occurrence of non-cancer outcomes, neurologic and respiratory symptoms. The cohort is routinely linked to cancer registries in IA and NC and vital statistics to identify cancer cases and deaths, and has also been linked to the U.S. Renal Data System to identify participants with end stage renal disease. We also collected buccal-cell samples for genetic research from 40% of participants, as well as from those with some specific incident cancers and other conditions, and conducted a dietary survey in 1999-2003. We conducted in-depth pesticide exposure assessments for selected chemicals in sub-samples of the cohort. Results of these assessments have been used to validate study questionnaires and inform exposure classification. NIEHS researchers lead AHS research on farming exposures in relation to diverse non-cancer outcomes, including neurological diseases and symptoms (Parkinson's, Alzheimer's, depression, neurobehavioral function, suicide, and amyotrophic lateral sclerosis), respiratory outcomes (e.g., asthma), cardiovascular disease (heart attack, stroke), diabetes (gestational and adult onset), kidney and thyroid disease, autoimmune diseases (rheumatoid arthritis), age-related macular degeneration, fatal injury, and reproductive outcomes (infertility, fibroids and endometriosis). New research on neurologic outcomes includes analyses on pre-motor symptoms and validation of incident Parkinsons disease. In 2015, the AHS started a new sub-study on pesticides in relation to dementia and Alzheimer's disease, a collaboration led by investigators at Duke University. We have screened cognitive function in nearly 2500 elderly participants and identified 16% with possible Alzheimers disease or other dementias. Home visits, blood collection, and case validation efforts are underway. Findings on enrollment pesticides and cognitive function were recently submitted for publication, and analyses are ongoing. NIEHS research on respiratory outcomes includes extensive published findings on pesticides, wheeze and asthma, as well as an in-depth study of respiratory diseases involving a sub-cohort of applicators and spouses (The Lung Health Study; see report by S London). In this sub-study, we have seen inverse associations of perinatal and early childhood farm exposures with atopy, and an association of childhood raw milk consumption with higher lung function in adulthood. Recently published findings show house dust endotoxin is associated with asthma phenotype and higher counts of peripheral white blood cells. New research describes the house dust microbiome in relation to farm exposures and asthma, and a novel association of specific pesticides with sleep apnea. Ongoing research is focused on genetic risk scores for pulmonary function, and DNA methylation in relation to pesticide use. Our recent research on pesticides and incident rheumatoid arthritis (RA) in female spouses identified several associations, including specific pesticides, chemical fertilizers, and solvents. In addition to published findings of specific pesticide associations with RA in male farmers, our new findings, submitted for publication, confirm that incident RA is associated with chemical fertilizers and solvents in a larger sample including both famers and spouses. We are also conducting analyses of pesticides in relation to anti-nuclear autoantibodies in 700 male farmers. Ongoing work is identifying participants with related autoimmune diseases, including systemic lupus erythematosus, to allow further investigations. In the Growth and Puberty Study, we explored the feasibility of measuring early puberty markers (hormones in urine and saliva, height velocity, Tanner staging) in 60 children. Hormone assays are completed and a paper showing that certain hormones are elevated at least several months before self-reported and physiologic measures (e.g. Tanner sating and onset of menses) is under review. A new analysis is exploring hormone levels in relation to children's potential pesticide exposure. Using a recently completed case confirmation and validation of self-reported thyroid disease, we have identified pesticide associations with incident hypothyroidism in female spouses and male farmers, confirming earlier studies of mostly prevalent cases. These findings have been recently published. Findings on pesticide associations with incident hyperthyroidism were largely null; a manuscript has been submitted for publication. The AHS continues to participate in large data pooling projects through the NCI-sponsored Cohort Consortium, and has contributed to several large-scale pooling projects evaluating genetic and lifestyle/environmental risks for several cancers (e.g. breast, thyroid, ovarian cancers). The AHS is also one of the founding members of the Agricultural Cohort Consortium (AGRICOH), and we are collaborators in new and ongoing research on asthma and neurologic outcomes. In the future, this collaboration will enhance our ability to assess rare exposures and outcomes, such as autoimmune diseases. Although cohort members have lower rates of death from some chronic diseases than the general population, we have previously observed elevated mortality from some specific causes, including injury and some cancers. In new analyses with more deaths, we have confirmed these findings and identified elevated standardized and causal mortality ratios for additional causes; findings have been presented at national meetings, and a manuscript will be submitted shortly. Through linkage to the U.S. Renal Data System, we have previously published findings on pesticides and end-stage renal disease in farmers and spouses. Given increasing rates of renal disease with aging, and an epidemic of unexplained renal failure in global agriculture, we are planning new linkages to study renal failure in the AHS. Half of the cohort is now over age 65, and we have new work underway to link AHS to administrative data on health outcomes in Medicare-eligible AHS participants. These data will enable studies of diseases that are difficult to study without validation and in participants lost to follow-up, reducing participant burden while facilitating research on aging-related diseases and allowing studies of clinical biomarkers such as measures of renal dysfunction. Over the years, the Agricultural Health Study has contributed to our knowledge on potential health effects of exposures associated with pesticides use and other farming activities. This continuously serves our ultimate goal to improve the health of US farmers and their family members.